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    Heme Metabolism by DR Roomi

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    Mudassar Roomi
    The document summarizes heme synthesis and porphyrias. It discusses the 8 enzymatic steps of heme synthesis that occur within mitochondria. Porphyrias result from deficiencies in these enzymes that can cause acute or chronic conditions. The document also covers bilirubin metabolism, the breakdown of heme to bilirubin in the liver, enterohepatic circulation, and causes of jaundice like prehepatic, intrahepatic, and posthepatic hyperbilirubinemia.

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    Heme Metabolism by DR Roomi

    Uploaded by

    Mudassar Roomi
    349 views24 pages
    The document summarizes heme synthesis and porphyrias. It discusses the 8 enzymatic steps of heme synthesis that occur within mitochondria. Porphyrias result from deficiencies in these enzymes that can cause acute or chronic conditions. The document also covers bilirubin metabolism, the breakdown of heme to bilirubin in the liver, enterohepatic circulation, and causes of jaundice like prehepatic, intrahepatic, and posthepatic hyperbilirubinemia.

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    Heme Metabolism by Dr Roomi

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    The document summarizes heme synthesis and porphyrias. It discusses the 8 enzymatic steps of heme synthesis that occur within mitochondria. Porphyrias result from deficiencies in these enzymes that can cause acute or chronic conditions. The document also covers bilirubin metabolism, the breakdown of heme to bilirubin in the liver, enterohepatic circulation, and causes of jaundice like prehepatic, intrahepatic, and posthepatic hyperbilirubinemia.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    349 views24 pages

    Heme Metabolism by DR Roomi

    Uploaded by

    Mudassar Roomi
    The document summarizes heme synthesis and porphyrias. It discusses the 8 enzymatic steps of heme synthesis that occur within mitochondria. Porphyrias result from deficiencies in these enzymes that can cause acute or chronic conditions. The document also covers bilirubin metabolism, the breakdown of heme to bilirubin in the liver, enterohepatic circulation, and causes of jaundice like prehepatic, intrahepatic, and posthepatic hyperbilirubinemia.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    of 24

    HEME SYNTHESIS

    BY DR. MUDASSAR ALI ROOMI

    Within Mitochondria

    HEME SYNTHESIS AND PORPHYRIAS


    ALA synthase

    GLYCINE + SuccinylCoA d-aminolevulinic acid(ALA) Porphobilinogen(PBG)

    ALA dehydratase

    ALA-dehydratase Deficiency porphyria Acute intermittent Congenital erythropoietic porphyria Prophyria cutanea tarda

    hydroxymethylbilane
    uroporphyrinogen III coprophyrinogene III

    Hydoxymethylbilane synthase Porphyria

    Uroporphyrinogen III synthase 4 Uroporphyrinogen decarboxylase

    Protoporphyrinogene IX
    protoporphyrin IX Heme

    Coproporphyrinogen oxidase

    Herediatary coproporphyria
    Variegate porphyria Erythropoietic protoporphyria

    Protoporphyrinogen oxidase
    7

    Ferrochelatase

    QUESTIONS FROM HEME SYNTHESIS


    Proteins in which heme is present as a prosthetic group??? Substrates required for heme synthesis???? tissues in which heme synthesis occurs???? Rate limiting step of heme synthesis??? Lead inhibits which enzymes???? ALA-synthase is inhibited by ???? Co-enzyme of ALA-synthase??? ALA-synthase is activated by????

    QUESTIONS FROM PERPHYRIAS


    Genetics of porphyrias??? Clinical manifestations of porphyrias???? Mechanism of photosensitivity seen in most of the porphyrias??? The most common of all the porphyrias???? Why ALA-synthase activity increases in porphyrias???? What is the treatment of an acute attack of porphyria????

    FATE OF RED BLOOD CELLS


    Life span in blood stream is 60-120 days. old and fragile RBCs are phagocytosed and are lysed. Normally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis. Lysis can also occur intravascularly (in blood stream) .

    QUESTION: rate limiting step in metbolism of bilirubin in liver????

    PATHWAY FOR RBC DESTRUCTION


    (Liver, Bone marrow, & Spleen)
    Phagocytosis & Lysis

    Hemoglobin

    Globin

    Heme

    Bilirubin

    Amino acids

    Fe2+

    Amino acid pool

    Recycled

    Excreted

    DEGRADATION OF HEME TO BILIRUBIN


    85% bilirubin is derived from heme as a result of RBC degradation. In normal adults this results in a daily load of 250-300 mg of bilirubin but liver has the ability to conjugate 3000mg /day of bilirubin.
    P450 cytochrome

    Normal plasma concentration of bilirubin is less then 1 mg/dl and jaundice occurs usually at conc. greater than 2mg/dl. bilirubin is Hydrophobic or water insoluble and is transported by albumin to the liver for further metabolism prior to its excretion. QUESTION: function of bilirubin in mammals???

    unconjugated bilirubin

    Heme Degradation
    NADPH Fe+3 HEME O2 NADP+

    Heme Catabolism

    (opens the porphyrin ring)

    BILIVERDIN NADPH NADP+ BILIRUBIN

    BILIRUBIN diglucuronide

    BILE

    WHAT IS ENTEROHEPATIC CIRCULATION?

    JAUNDICE
    Due to Hyperbilirubinemia (greater than 2mg/dl):

    Two forms of bilirubin:


    Direct bilirubin: Conjugated with glucoronic acid and is soluble in water. Indirect bilirubin: unconjugated, insoluble in water. QUESTION: How do we determine bilirubin concentration????

    DIFFERENCES BETWEEN
    UNCONJUGATED BILIRUBIN Insoluble in water. Cannot be excreted in urine. Can deposit in brain. Plasma level increases in pre-hepatic jaundice. CONJUGATED BILIRUBIN Soluble in water. Can be excreted in urine. Cannot be deposited in brain. Plasma level increases in hepatic and post-hepatic jaundice.

    Hemolytic jaundice

    Hepatocellular jaundice

    Obstructive jaundice

    excess hemolysis

    unconjugated bilirubin (in blood) conjugated bilirubin (released to bile duct)

    unconjugated bilirubin (in blood) conjugated bilirubin (in blood)

    unconjugated bilirubin (in blood) conjugated bilirubin (in blood)

    HYPERBILIRUBINEMIA
    Increased plasma concentrations of bilirubin (> 2 mg/dl) occurs when there is an imbalance between its production and excretion Recognized clinically as jaundice

    PREHEPATIC (HEMOLYTIC) JAUNDICE


    Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis. Excess RBC lysis is commonly the result of hemolytic diseases, structurally abnormal RBCs (Sickle cell disease). High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

    INTRAHEPATIC JAUNDICE
    Impaired uptake, conjugation, or secretion of bilirubin Reflects a generalized liver (hepatocyte) dysfunction In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

    POSTHEPATIC JAUNDICE
    Caused by an obstruction of the biliary tree.

    Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma which causes itching. Characterized by paleor clay coloured stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)
    In a complete obstruction, urobilin is absent from the urine

    DIAGNOSES OF JAUNDICE

    NEONATAL JAUNDICE
    Common, particularly in premature infants Transient (resolves in the first 10 days) Due to immaturity of the enzymes involved in bilirubin conjugation High levels of unconjugated bilirubin are toxic to the newborn due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form QUESTION: which enzyme is deficient in cases of neonatal jaundice.

    DISSOCIATION CURVES

    DIFFERENCES BETWEEN
    HEMOGLOBIN MYOGLOBIN

    Located within RBCs. Composed of 4 polypeptide chains. One molecule of Hb has 4 heme molecules. One Hb molecule can bind with 4 O2 molecules. Affinity for O2 is comparatively less. O2 Hb dissociation curve is sigmoidal in shape. P50 is 26mmHg.

    Heart and skeletal muscle. Conposed of one polypeptide chain only. One molecule of myoglobin has one heme molecule. One molecule can bind with one O2 molecule. Affinity is comparatively more. O2 myoglobin dissociation curve is hyperbolic. P50 is 1mmHg.

    SHIFT OF THE CURVE

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